chrX-49030447-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006521.6(TFE3):c.1439G>C(p.Gly480Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,209,577 control chromosomes in the GnomAD database, including 2 homozygotes. There are 394 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G480E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., 16 hem., cov: 22)

Exomes 𝑓: 0.0010 ( 2 hom. 378 hem. )

Consequence

TFE3
NM_006521.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.50

Publications

4 publications found

Variant links:

Genes affected

TFE3 (HGNC:11752): (transcription factor binding to IGHM enhancer 3) This gene encodes a basic helix-loop-helix domain-containing transcription factor that binds MUE3-type E-box sequences in the promoter of genes. The encoded protein promotes the expression of genes downstream of transforming growth factor beta (TGF-beta) signaling. This gene may be involved in chromosomal translocations in renal cell carcinomas and other cancers, resulting in the production of fusion proteins. Translocation partners include PRCC (papillary renal cell carcinoma), NONO (non-POU domain containing, octamer-binding), and ASPSCR1 (alveolar soft part sarcoma chromosome region, candidate 1), among other genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

TFE3 Gene-Disease associations (from GenCC):

intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
X-linked syndromic complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

TFE3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009028733).

BP6

Variant X-49030447-C-G is Benign according to our data. Variant chrX-49030447-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 723210.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 71 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006521.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFE3	NM_006521.6	MANE Select	c.1439G>C	p.Gly480Ala	missense	Exon 10 of 10	NP_006512.2
	TFE3	NM_001282142.2		c.1124G>C	p.Gly375Ala	missense	Exon 10 of 10	NP_001269071.1	B4DIA5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFE3	ENST00000315869.8	TSL:1 MANE Select	c.1439G>C	p.Gly480Ala	missense	Exon 10 of 10	ENSP00000314129.7	P19532-1
TFE3	ENST00000874969.1		c.1331G>C	p.Gly444Ala	missense	Exon 10 of 10	ENSP00000545028.1
TFE3	ENST00000912302.1		c.1253G>C	p.Gly418Ala	missense	Exon 10 of 10	ENSP00000582361.1

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

111289

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000523

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000575

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00114

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.000331

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000774

Gnomad OTH

AF:

0.000671

GnomAD2 exomes

AF:

0.000818

AC:

149

AN:

182112

AF XY:

0.000847

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.000577

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000943

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.00101

AC:

1113

AN:

1098236

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

378

AN XY:

363604

show subpopulations

African (AFR)

AF:

0.000682

AC:

AN:

26403

American (AMR)

AF:

0.00125

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.000258

AC:

AN:

19382

East Asian (EAS)

AF:

0.000430

AC:

AN:

30206

South Asian (SAS)

AF:

0.000960

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.000148

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.000726

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00112

AC:

943

AN:

842130

Other (OTH)

AF:

0.000629

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000638

AC:

AN:

111341

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

AN XY:

33541

show subpopulations

African (AFR)

AF:

0.000522

AC:

AN:

30680

American (AMR)

AF:

0.000574

AC:

AN:

10444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00114

AC:

AN:

3497

South Asian (SAS)

AF:

0.000371

AC:

AN:

2694

European-Finnish (FIN)

AF:

0.000331

AC:

AN:

6046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000775

AC:

AN:

52932

Other (OTH)

AF:

0.000662

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000509

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.00102

AC:

124

EpiCase

AF:

0.00120

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.92

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.018

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.51

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.20

PhyloP100

-1.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.22

REVEL

Benign

0.039

Sift

Benign

0.33

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.058

MVP

0.082

MPC

0.035

ClinPred

0.0071

GERP RS

-7.9

Varity_R

0.041

gMVP

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over